The gastrointestinal (GI) tract is the largest producer of serotonin (5-hydroxytryptamine (5-HT)) in the body, and as such it is intimately connected with GI function and physiology. Serotonin produced by enterochromaffin (EC) cells is an important enteric mucosal signaling molecule and has been implicated in a number of gastrointestinal disorders or conditions, including inflammatory bowel disease and irritable bowel syndrome.
Alosetron (LOTRONEX), a 5-HT3 receptor antagonist, became the first agent approved by the US Food and Drug Administration for the treatment of diarrhea-predominant IBS in 2000. However, the drug has demonstrated a difficult post-approval side effect profile that has resulted in a temporary market withdrawal. Meanwhile, activation of the serotonin 5-HT2B receptor is linked to cardiac valvulopathy and pulmonary hypertension (Fitzgerald et al. Mol Pharmacol. 2000; 57: 75-81; Setola et al. Mol Pharmacol. 2005 68:20-33, Launay J et al. Nat Med 2002 8: 1129-1135), and attenuation of 5-HT2B receptor signaling may prevent and/or reverse cardiopulmonary disorders (Janssen et al. Biomed Res Int. 2015; 2015:438403; Rothman et al. Expert Opin Drug Saf. 2009 May; 8(3):317-29).
There remains a need for agents that can safely modulate serotonin receptors (5-hydroxytryptamine receptors or 5-HT receptors) for the treatment of gastrointestinal and cardiopulmonary disorders or conditions.